July 9-14, 2000
The natural history chapter reminds us that liver fibrosis progression rate is the major surrogate endpoint for disease severity. HCV is a curious disease with a major aging phenomena. Infected at 5 years of age or at 40 years, the fragile subject will have cirrhosis at 50 years of age. This must be explained to the patient.
I have also liked the discussion of sexual transmission. There is a very pragmatic message here. We all agree to reduce the anxiety among spouses, saying that the risk is minimal and a condom is not mandatory. But we also have to say that the exposure to blood is possible during sexual intercourse. The examples of the authors, taken from the HIV experience, are excellent. One could also add the possible role of herpes infection. Therefore, condoms must be recommended for sexual intercourse during certain periods, especially in the presence of ulcerations or for anal intercourse.
For the chapter concerning HCV-RNA quantification, the HCV clinician would emphasize that HCV viral load has not the same importance that HIV viral load has in the management of HIV disease. As stated several times by the authors, HCV viral load is not associated with the severity of the disease (i.e., fibrosis progression rate). Also in treatment strategy, we are very disappointed by the predictive values of quantitative PCR. Indeed, there is a correlation between the 4-week impact of treatment and the sustained response, but this correlation is too weak to permit 100% positive or predictive values. Furthermore, the prediction made by viral kinetics for patients treated with 24 weeks of an IFN-ribavirin combination regimen are false if patients are treated for 48 weeks. Maybe we have to remind ourselves that HCV is not a blood disease but a liver disease. Blood kinetics are perhaps unrelated to liver kinetics.
The chapter concerning co-infection with HIV raises one very important clinical problem: the need for liver transplantation of HIV-HCV co-infected patients who are dying from liver insufficiency, hemorrhage or liver cancer. Trials are certainly needed, but I am convinced that we now have the skill to manage both viruses after the transplantation. Too many young patients are dying these days. Just do it . . . ?
The chapters on therapies are also very good. Physicians must also know that interferon is very effective as an antifibrotic agent. While waiting for new anti-viral drugs, non-responders can be treated with interferon alone in order to reduce fibrosis progression. In patients co- infected with HCV-HIV, this maintenance therapy must be considered in rapid fibrosers. The chapter on new therapies is particularly interesting to read. As an experimented trialist I would temper the indirect comparisons between different PEG-interferons. We have been disappointed already by preliminary results and indirect comparisons between interferons. We know now that there are at least five independent risk factors of viral response. Therefore, only large randomized trials can prove that one PEG-interferon is better than another one. A small difference in genotype can confound any comparison. The remarks concerning patents and other industrial factors have to be explained to patients and naive doctors.
The Research and Policy Recommendations are sound and important. The call for increased basic and clinical research funding, physician and patient education, studies to answer epidemiology and natural history questions in select patient populations, and novel antiviral treatments will have a tremendous impact on the future of this disease.
In a clinical conclusion, I will certainly recommend the prescription of this report, reimbursed or not.